Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)
Part II. Cancer stem cells
EMT is a critical cellular programme in normal development that is co-opted by epithelial cancer cells and is required for progression along the metastasis cascade. It provides cancer cells with mesenchymal traits critical for metastatic processes, including invasion, dissemination and colonization. The activation of EMT in epithelial cancers requires induction by stimuli present within the tumour microenvironment, subsequent activation of intracellular signalling networks and the stimulation of core transcription factors that orchestrate the regulation of many effector molecules involved in the processes of cell adhesion, mesenchymal differentiation, migration and invasion. The concept of epithelial – mesenchymal plasticity encompasses the adaptive changes that cancer cells can undergo along the EMT – MET axis and defines the high degree of flexibility that cancer cells exhibit between the epithelial and mesenchymal states. This cellular plasticity is evident in the strong association between cells that have undergone EMT and CSCs, a subpopulation of cancer cells capable of self-renewal that is an important contributor to tumour recurrence and metastasis. Hypoxia, a microenvironmental condition prominent in many solid tumours, induces EMT and is important for the regulation of CSCs and cancer cell metastasis. Finally, EMT plays an important role in the acquisition of treatment resistance, a situation that leads to tumour recurrence and metastasis and involves cancer cells with CSC properties. Therefore, targeting of cancer cells that have undergone EMT represents an important therapeutic avenue for the control and potential elimination of metastatic disease.
Bao, B., Azmi, A.S., Ali, S., Ahmad, A., Li, Y., Banerjee, S., et al., 2012. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochim Biophys Acta 1826, 272 – 296.
Chaffer, C.L., Weinberg, R.A. 2011. A perspective on cancer cell metastasis. Science 331, 1559 – 1564.
Chang, J.T, Mani, S.A. 2013. Sheep, wolf, or werewolf: cancer stem cells and the epithelial-to-mesenchymal transition. Cancer Lett 341, 16 – 23.
Chiche, J., Ilc, K., Laferriиre, J., Trottier, E., Dayan, F., Mazure, N.M., et al., 2009. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 69, 358 – 368.
De Craene, B., Berx, G. 2013. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97 – 110.
Gao, D., Vahdat, L.T., Wong, S., Chang, J.C., Mittal, V. 2012. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res. 72, 4883 – 4889. Gatenby, R.A, Gillies, R.J. 2004. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891 – 899.
Gatenby, R.A, Gillies, R.J. 2008. A microenvironmental model of carcinogenesis. Nat. Rev. Cancer 8, 56 – 61.
Hanahan, D., Coussens, L.M. 2012. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309 – 322.
Hill, R.P., Marie-Egyptienne, D.T, Hedley, D.W. 2009. Cancer stem cells, hypoxia and metastasis. Semin. Radiat. Oncol. 19, 106 – 111.
Holohan, C., Van Schaeybroeck, S., Longley, D.B, Johnston, P.G. 2013. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714 – 726.
Kalluri, R. 2009. EMT: when epithelial cells decide to become mesenchymal-like cells. J. Clin. Invest. 119, 1417 – 1419.
Kalluri, R., Weinberg, R.A. 2009. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420 – 1428.
Kang, Y., Pantel, K. 2013. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23, 573 – 581.
Krebs, M.G., Metcalf, R.L., Carter, L., Brady, G., Blackhall, F.H., Dive, C. 2014. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat. Rev. Clin. Oncol. 11, 129 – 144.
Ksiazkiewicz, M., Markiewicz, A., Zaczek, A.J. 2012. Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology 79, 195 – 208.
Lamouille, S., Subramanyam, D., Blelloch, R., Derynck, R. 2013. Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr. Opin. Cell Biol. 25, 200 – 207.
Lamouille, S., Xu, J., Derynck, R. 2014. Molecular mechanisms of epithelialmesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178 – 196.
Lee, J.M., Dedhar, S., Kalluri, R., Thompson, E.W. 2006. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J. Cell Biol. 172, 973 – 981.
Lendahl, U., Lee, K.L., Yang, H., Poellinger, L. 2009. Generating specificity and diversity in the transcriptional response to hypoxia. Nat. Rev. Genet. 10, 821 – 832.
Lock, F.E., McDonald, P.C., Lou, Y., Serrano, I., Chafe, S.C., Ostlund, C., et al., 2013. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene 32, 5210 – 5219.
Lou, Y., McDonald, P.C., Oloumi, A., Chia, S., Ostlund, C., Ahmadi, A., et al., 2011. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 71, 3364 – 3376.
Marie-Egyptienne, D.T., Lohse, I., Hill, R.P. 2013. Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia. Cancer Lett. 341, 63 – 72.
McDonald, P.C., Winum, J.Y., Supuran, C.T, Dedhar, S. 2012. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget. 3, 84 – 97.
McIntyre, A., Patiar, S., Wigfield, S., Li, J.L., Ledaki, I., Turley, H. et al. 2012. Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. Clin. Cancer Res. 18, 3100 – 3111.
Murphy, D.A, Courtneidge, S.A. 2011. The ‘ins’ and ‘outs’ of podosomes and invadopodia: characteristics, formation and function. Nat. Rev. Mol. Cell Biol. 12, 413 – 426.
Neri, D., Supuran, C.T. 2011. Interfering with pH regulation in tumours as a therapeutic strategy. Nat. Rev. Drug Discov. 10, 767 – 777.
Nguyen, D.X., Bos, P.D, Massague, J. 2009. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274 – 284.
Nieto, M.A. 2013. Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342, 1234850.
Parks, S.K., Chiche, J., Pouyssegur, J. 2011. pH control mechanisms of tumor survival and growth. J. Cell Physiol. 226, 299 – 308.
Pattabiraman, D.R., Weinberg, R.A. 2014. Tackling the cancer stem cells – what challenges do they pose? Nat. Rev. Drug Discov. 13, 497 – 512.
Philip, B., Ito, K., Moreno-Sanchez, R., Ralph, S.J. 2013. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 34, 1699 – 1707.
Scheel, C., Weinberg, R.A. 2012. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396 – 403.
Tam, W.L., Weinberg, R.A. 2013. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat. Med. 19, 1438 – 1449.
Thiery, J.P. 2002. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442 – 454.
Thiery, J.P., Acloque, H., Huang, R.Y., Nieto, M.A. 2009. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871 – 890.
Tsai, J.H., Yang, J. 2013. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 27, 2192 – 2206.
Wan, L., Pantel, K., Kang, Y. 2013. Tumor metastasis: moving new biological insights into the clinic. Nat. Med. 19, 1450 – 1464.
Yang, J., Weinberg, R.A. 2008. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818 – 829.